Effect of combinations of drugs on all cause mortality in patients with ischaemic heart disease: nested case-control analysis
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7499.1059 (Published 05 May 2005) Cite this as: BMJ 2005;330:1059
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Hippisley-Cox and Coupland conclude that the addition of angiotensin
converting enzyme inhibitors (ACEI) to combinations of drugs, conferred no
additional benefit in their study of patients in primary care with
ischaemic heart disease. However such a conclusion should be made with
caution. From their data can be seen that ACEI were given to the patients
with the highest risk of death. A higher percentage of those that died
were treated with ACEI and the greatest improvement in risk of death after
adjustment for risk factors were seen in the patients treated with ACEI.
Therefore it is possible that ACEI were given to those with the most
severe disease also within each comorbidity group, for instance to
diabetic patients with kidney disease and to patients with the most severe
heart failure. Therefore the study can give no indication of the crucial
question whether the outcome would have been equally good for the probably
most diseased group of 463 patients that were given statins, aspirin,
betablockers and ACEI if they had not been given ACEI. Replacement of yes
or no for comorbidity factors with more discriminating variables, such as
presence of microalbuminuria and a severity measure for heart disease,
would probably have improved the study. However, this can not replace the
quality of a randomised, placebo controlled study comparing the effect of
adding ACEI to the other study drugs. Therefore the study by Hippisley-Cox
and Coupland adds no new knowledge to how patients with ischaemic heart
disease in primary care should be treated.
Competing interests:
None declared
Competing interests: No competing interests
I'm afraid this study leads to much generalization. First, I'm
concerned about the ACE-I,(Angiotensin Converting Enzyme), data, which
flies in the face of convention. Second, without actual data in front of
me, I have to guess at the meaning of the ACE-I data.
As the EUROPA, PROGRESS, ANBP, PEACE, TRACE, SAVE, and HOPE studies
have shown, there is a great disparity in ACE-I efficacy. As Doulton, He,
and MacGregor state in their review of ACE/ARB trials, ACE I Trials were
described as, "However, the majority of these studies used submaximal
doses or once-daily dosing of shorter-acting ACE inhibitors..."
(Hypertension. 2005 May;45(5):880-6. Epub 2005 Apr 4.) It has long been
known that the more efficacious trials of ACE-I utilized a large dose, as
the perindopril investigators found out in PROGRESS & EUROPA.
Trandalopril investigators also saw this disparity in PEACE & TRACE.
So, I ask, what were the ACE-I doses in this trial?
Another consideration is that the order in which these drugs were
given, Beta-Blockers first? Or ACE-I first? If one gives a Beta-Blocker
first, the drop in BP,(blood pressure), will for the most part, urge
clinicians to give a lower dose of ACE-I subsequently. This, as the
authors above state, are, "submaximal doses".
I find it somewhat cavalier to come to the conclusions
that Julia Hippisley-Cox and Carol Coupland came to without a better
understanding of the raw data. On the other hand, my most sincere
apologies if this was taken into account.
Then, there is the concept of equality in ACE-I's. Though a larger
dose is good, does it still have the effect than another ACE-I might have?
The MITRA-Plus Trial serves as an example here. This is, as an earlier
response indicates, the possibility of another disparity.
I look forward to an accounting of this data, as it will clear up
many suppositions, both past and present.
Respectfully,
Frank A. Snyder, M.S., M.D.
Competing interests:
None declared
Competing interests: No competing interests
The majority of patients with a chronic disease are taking more than
one prescribed drug and it is very important to explore the repurcussions
of drug combinations. I applaud Julia Hippisley-Cox and Carol Coupland for
their recent publication which further explores such combinations (Effect
of combinations of drugs on all cause mortality in patients with ischaemic
heart disease: nested case-control analysis. BMJ 2005;330:1059-63). In the
setting of ischemic heart disease the combination of statins, aspirin, and
beta-blockers provided the greatest protection from all-cause mortality.
This is not very surprising but it is noteworthy that the addition of an
angiotensin converting enzyme (ACE) inhibitor did not provide further
protection. This is of interest because the issue of equality among the
ACE inhibitors is not yet settled. While many of their actions are class
effects, some studies indicate that perhaps all ACE inhibitors are not
equal. I wonder if the authors would be able to analyze their dataset to
explore possible differences among the ACE inhibitors. I urge the authors
to inform the readers of which ACE inhibitors were found in the dataset
and how often each was prescribed. We all prescribe ACE inhibitors and it
is important to know which ACE inhibitors can further reduce all-cause
mortality, if any.
Competing interests:
Within the past five years RR has received the following reimbursements: Wyeth-Ayerst for participation in programs on ramipril; Pfizer for attendence at symposiums on quinapril; Pfizer for consulting and participation in programs on atorvastatin. RR also has relationships with Sandoz, Sankyo, and Otsuka for products not involved in this published report.
Competing interests: No competing interests
In the recent community based analysis by Hippisley-Cox and Coupland
it has been indicated that the addition of an angiotensin converting
enzyme inhibitor doesn’t confer any additional survival’s improvement in
high risk patients with cardiovascular disease (CVD) (1).
In the population, as long as in the single patient, risk-benefit
ratio of a pharmacological treatment is the major determinant for current
guidelines. Even so, sanitary expense has its right counterpart.
We shouldn’t forget that statins are not so cheap.
LDL cholesterol (LDL-C) still remains the primary target and
randomised controlled trials have shown significant improvement in
secondary prevention of patients undergoing LDL-lowering therapy (2).
Every patient is also candidate of total lifestyle changes (TLC) and this
regardless of LDL-C level according to the usual association with
lifestyle-related risk factors (e.g. obesity, physical inactivity,
elevated triglycerides, low HDL cholesterol or metabolic syndrome) (3).
Benefits deriving from an healthy eating pattern on CVD determinants
are well demonstrated (4) and moderate weight loss actively participates
to a reduction of visceral fat-related inflammatory background (5).
Moreover in the recent issue of BMJ greater evidence has been given to
diet-linked longevity (6).
Implications of recent clinical trials have also suggested an LDL-C
goal of <70 mg/dL (<1.8 mmol/L) as a therapeutic option of
additional benefit (3).
Achieving this newly purposed LDL-C target is probably far from being
possible through the only action of TLC. By the other hand their
effectiveness shouldn’t be underestimated, above all in term of believable
drug dose lowering.
Statins of new generation looks safer (7) but lower therapeutic doses
may reduce both side effects’ occurring and costs.
Thus lifestyle changes are a clinical imperative too.
REFERENCES
1. Hippisley-Cox J and Coupland C. Effect of combinations of drugs
on all cause mortality in patients with ischaemic heart disease: nested
case-control analysis. BMJ 2005;330;1059-1063
doi:10.1136/bmj.330.7499.1059
2. Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. Executive Summary of The Third Report of The
National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult
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RJ et al. AHA Dietary Guidelines: revision 2000: A statement for
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7. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E,
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across doses (STELLAR* Trial). Am J Cardiol. 2003; 2:152-60
Competing interests:
None declared
Competing interests: No competing interests
Sirs,
Once again, based on EBM, we should agree with the statement of authors
who write “Combinations of statins, aspirins, and blockers are associated
with the greatest reduction in all cause mortality in patients with a
first diagnosis of ischaemic heart disease”, because of the results
gathered in “a case-control analysis including 13.029 patients nested
within an open prospective cohort study with 1.18 million patients” (1).
Apart from my surprise due to the inclusion in their study also of other 9
(sic) patients, added to 13.020 (really jet a sufficiently large number,
if accuretely monitored , also from the “clinical” viewpoint, isn’t it?), I
wonder if the authors are acquainted or not with the Single Patient Based
Medicine (2, 3) (www.semeioticabiofisica.it). In fact, a 48-year-long
clinical experience allows me to state that there aren’t diseases, but
diseased “single” individuals, with their very particular biophysical-semeiotics constitutions. For instance, without the well-known common
risk factors (but involved by a lot of others, biophysical semeiotics in
nature, overlooked surely by the paper authors), and in “apparently”
healthy conditions, according to acadèmic physical semeiotics, about 5
years ago, I had a myocardial infarct, followed by heart arrest.
Because my cholesterol blood levels, according to ITALIAN physiological
concentrations, of course (!!!), were and are always normal, I never used
statins, which are not innocent drugs (4, 5). Why should my colleagues-friends
add statins to my therapy when myocardial infarction happened? On the
contrary, since the disease began, I am under therapy also with angiotensin
converting enzyme inhibitor, because evaluated clinically (6) my ACE
system at cardiovascular levels showed hypertonus, now disappeared.
1) Hippisley-Cox j., Coupland c. For newly diagnosed ischaemic heart
disease give a statin, aspirin, and blocker. BMJ 2005;330 (7 May),
doi:10.1136/bmj.330.7499.0-a
2) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-
Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la
definizione della Single Patient Based Medicine. Ediz. Travel Factory,
Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm
3) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La
Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina.
Travel Factory SRL., Roma, 2004.
http://www.travelfactory.it/semeiotica_biofisica.htm
4) Stagnaro-Neri M., Stagnaro S., Carenza di Co Q10 secondaria a terapia
ipolipidemmizante diagnosticata con la Percussione Ascoltata. Settimana
Italiana di Dietologia, 9-13 Aprile 1991, Merano. Atti, pg. 65. Epat. 37,
17 1990
5) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Coenzyme Q
deficiency Syndrome. VI Int. Symp., Biomedical and clinical aspects of
Coenzyme Q. Rome, January 22.24, Chairmen K. Folkers, G.L. Littaru, T.
Yamagani, Abs., pg. 105, 1990.
6) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione
clinica del picco precoce della secrezione insulinica di base e dopo
stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo
attivazione del sistema renina-angiotesina circolante e tessutale. Acta
Med. Medit. 13, 99, 1997.
Competing interests:
None declared
Competing interests: No competing interests
following line in the Discussion: ".., confounding by indication could have [sic] occurred if patients with a better prognosis were more likely to be prescribed different combinations of treatments."
Evidently, high rather than low cholesterol levels are linked with greater statin use and this selects the high cholesterol group where early death
from heart failure is less Horwich
TB et al (1) and where general mortality in elderly is lower Weverling-Rijnsburger
AW et al (2) and Schatz
IJ et al (3).
It is thus unfortunate that the study at hand states that therapy including statins "improve[s] survival" rather than stressing the simple point of selection bias, i.e. of not being in the "low cholesterol" group of elderly where increased mortality may well be concentrated and where cholesterol-lowering therapy was not indicated.
This cohort study could lead to 'could have' medicine while in a high-risk population of virtually identical age, the placebo controlled PROSPER
(4) study (surprisingly, omitted as reference) found absolutely no mortality benefit but increased cancer in a statin group with fewer smokers.
1. Horwich TB, Hamilton MA, et al. Low
serum total cholesterol is associated with marked increase in mortality
in advanced heart failure. J Card Fail. 2002 Aug;8(4):216-24. Medline
12397569.
2. Weverling-Rijnsburger AW, Blauw GJ et al. Total
cholesterol and risk of mortality in the oldest old. Lancet. 1997 Oct
18;350(9085):1119-23. Medline 9343498.
3. Schatz IJ, Masaki K et al. Cholesterol
and all-cause mortality in elderly people from the Honolulu Heart Program:
a cohort study. Lancet. 2001 Aug 4;358(9279):351-5. Medline 11502313.
4. Shepherd J, Blauw GJ et al. Pravastatin
in elderly individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. Medline 12457784.
Competing interests:
None declared
Competing interests: No competing interests
ACE Inhibitors and Ischaemic heart disease
While the issue of adding an angiotensin converting enzyme (ACE)
inhibitor to the standard regimen of antiplatelets, statins and Beta
blockers in patients with ischaemic heart disease particularly without
left ventricular dysfunction remains controversial in the light of
conflicting results from randomized controlled trials like HOPE, EUROPA(1)
(supporting use) and PEACE(2)(not supporting), what is an observational study
with nested case-control analysis(3) prone for bias and confounding as
acknowledged by authors Hippisley-Cox and Coupland themselves going to
achieve? More sound is a meta-analysis of HOPE, PEACE, and EUROPA data
which showed significant reductions in mortality, and reinfarction.(4)
When evidence from randomized controlled trials is available, champions of
evidence based medicine like BMJ should seriously consider the clinical
relevance of such an observational study, notwithstanding its statistical
robustness, to clinical practice.
With the evidence available the benefit of doubt should be in favour of
the use of ACE inhibitors and a case can only be made for withholding ACE
inhibitors when patients satisfy the inclusion criteria of PEACE trial.(5)
References:
1. Fox KM; The EURopean Trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease Investigators. Efficacy of
perindopril in reduction of cardiovascular events among patients with
stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-
788.
2. The PEACE Trial Investigators. Angiotensin-converting–enzyme inhibition
in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.
3. Hippisley-Cox J and Coupland C. Effect of combinations of drugs on all
cause mortality in patients with ischaemic heart disease: nested case-
control analysis. BMJ 2005;330;1059-1063
4. Yusuf S and Pogue J. ACE inhibition in stable coronary artery disease.
N Engl J Med. 2005;352(9):937-9
5. Pitt B. ACE inhibitors for patients with vascular disease without left
ventricular dysfunction — may they rest in peace? N Engl J Med.
2004;351:2115-2117.
Competing interests:
Has had many free lunches sponsored by various pharmaceutical companies promoting various ACE inhibitors.
Competing interests: No competing interests